Strong evidence suggests that gender differences exist in drug abuse and dependence. Relapse to drug abuse following prolonged abstinence is a significant impediment in the long-term treatment of drug dependence. Although multiple factors have been identified in relapse, there remains a lack of understanding of the role of sex differences in the process of relapse following withdrawal from chronic drug self-administration. Craving states produced by conditioned-cues, stress, and drugs themselves, are all believed to be critically involved in relapse to compulsive drug-seeking behavior. Reinstatement of extinguished operant responding is a well-established animal model of relapse that has clinical relevancy. In this model, three experimental paradigms allow for the reinstatement of drug-seeking behavior (as measured by operant responding on a previously drug-paired lever) to levels that approximate those seen during primary reinforcement. The three models include a) re-exposure to discrete stimuli (tone+light) previously paired with cocaine infusions; b) exposure to brief stress (footshock); and c) noncontingent administration of cocaine itself. In this project, studies are proposed to examine sex differences in these various forms of reinstatement and to test the general hypothesis that female and male rats are uniquely susceptible to the different forms of reinstatement. Furthermore, we will establish the degree to which selective pharmacological compounds will differentially attenuate reinstatement in females vs. males. These experiments provide an integrated approach to understanding sex differences in relapse to cocaine-seeking behavior. Information gained from this project will also provide direction for other components of the SCOR and help direct the future development of gender-specific treatments for craving and relapse.